3D models of the bone marrow in health and disease: yesterday, today, and tomorrow
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Prospective Article
3D models of the bone marrow in health and disease: yesterday, today, and tomorrow Annamarija Raic, Toufik Naolou, Anna Mohra, Chandralekha Chatterjee, and Cornelia Lee-Thedieck, Karlsruhe Institute of Technology (KIT), Institute of Functional Interfaces, 76344 Eggenstein-Leopoldshafen, Germany Address all correspondence to Cornelia Lee-Thedieck at [email protected] (Received 3 August 2018; accepted 10 September 2018)
Abstract The complex interaction between hematopoietic stem cells (HSCs) and their microenvironment in the human bone marrow ensures a life-long blood production by balancing stem cell maintenance and differentiation. This so-called HSC niche can be disturbed by malignant diseases. Investigating their consequences on hematopoiesis requires a deep understanding of how the niches function in health and disease. To facilitate this, biomimetic models of the bone marrow are needed to analyze HSC maintenance and hematopoiesis under steady state and diseased conditions. Here, 3D bone marrow models, their fabrication methods (including 3D bioprinting), and implementations recapturing bone marrow functions in health and diseases are presented.
Introduction The red bone marrow, located in the cavities of the trabecular regions in long bones, represents a complex blood and bone cell-producing organ. Blood cells develop from immature hematopoietic stem and progenitor cells (HSPCs) and ensure the completion of several essential tasks like immune function, blood clotting or oxygen transport. Whereas most mature blood cells undertake their tasks mainly outside of the bone marrow, the only place where hematopoietic stem cells (HSCs) execute their functions (stem cell maintenance and blood cell production by differentiation) to guarantee lifelong blood production, is in their stem cell niche in the red part of the bone marrow.[1] Current studies revealed the existence of such niches at certain sites of the bone marrow. These niches are illustrated in a simplified form in Fig. 1. One of those is described as the endosteal niche, characterized by bone regenerating osteoblasts (OBs) located at the endosteal surface of bone.[1] OBs are able to regulate HSC function e.g., by activation of the Notch pathway and production of thrombopoietin (TPO), they are involved in controlling HSCs quiescence.[2,3] Another site for HSC niches was described close to the vascular structure near the endosteum, specified as arterioles, which have also an impact on HSC quiescence and thus form a unique arteriolar niche.[4] Nevertheless, dividing and non-dividing HSCs are mainly found in the perisinusoidal regions of the bone marrow.[5] Here, HSCs are in close proximity to blood vessel covering endothelial cells, which affect HSC dormancy and self-renewal via cell–cell contacts (e.g., via E-selectin). This region is generally referred to as the endothelial/perisinusoidal niche.[6,7] At this perivascular site, HSCs are in close contact
with enriched mesenchymal stromal cells (MSCs) which are subdivided into Leptin
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